Biology subjects

Talianidis, I.

Publications and source records attributed to Talianidis, I..

3 recordsLinked to original sources

bioRxiv2024

Setdb1 regulates proper differentiation of adult intestinal stem cells via restraining permissive chromatin structure and transcriptional variability

The histone methylase Setdb1 plays a pivotal role in embryonic stem cell maintenance and developmental lineage specification. However, its function in adult stem cells remains elusive. Here we show that conditional inactivation of Setdb1 in Lgr5+ intestinal stem cells alters the transcriptional programs of the progeny cell types and results in increased cell-to-cell transcriptional variability. Loss of Setdb1 blocked differentiation towards the absorptive enterocyte lineage, while the secretory cell types were only marginally affected due to the activation of alternative developmental trajectories. Setdb1 inactivation did not affect global H3K9 methylation at large heterochromatin domains but led to altered distribution of transposase-accessible chromatin regions, aberrant exposure of transcription factor binding sites and premature activation of differentiation-specific genes. The results demonstrate that Setdb1 regulates intestinal stem cell differentiation by fine-tuning chromatin accessibility in open euchromatin regions thereby controlling transcriptional variability between cells.

cell biology↗

bioRxiv2024

Invariant Natural Killer T cells control positively and negatively the development of hepatocellular carcinoma

The liver routinely encounters antigens from the gut, triggering pro- inflammatory responses. Unresolved inflammation can lead to liver damage, steatosis, fibrosis, cirrhosis, and eventually hepatocellular carcinoma (HCC). HCC is influenced by various immune cells, including invariant natural killer T (iNKT) cells, which exhibit both innate and adaptive immunity traits. Here, we examined iNKT cell dynamics in a diethyl-nitrosamine (DEN)-induced HCC mouse model. We observed a significant reduction in iNKT cell numbers in HCC livers due to apoptosis and impaired cytokine production. CD1d-deficient mice, which lack iNKT cells, displayed delayed tumor initiation and lower tumor and foci number. However, these tumors were larger in size and characterized by enhanced proliferation and immunosuppression. Interestingly, adoptive transfer of healthy iNKT cells post-tumor establishment reduced tumor burden, highlighting their potential therapeutic role. Our findings suggest that iNKT cells contribute to early HCC development, while in later stages they help to control tumor growth, thus underscoring their complex role in liver carcinogenesis. Further understanding of iNKT cell functions may inform novel immunotherapeutic strategies for HCC management.

immunology↗

bioRxiv2023

Endonucleosis mediates internalization of cytoplasm into the nucleus in senescent cells

Cellular senescence is driven by diverse effector programs, leading to irreversible growth arrest, DNA damage and complex secretomes. Here we show that, in liver-specific Setd8-KO mice, after mitogen treatment, a significant number of hepatocytes become senescent and display unusual features such as enlarged nuclei, chromosomal hyperploidy and nuclear engulfments progressing to the formation of intranuclear vesicles. These vesicles contain glycogen, cytoplasmic proteins and even entire organelles. We term this process "endonucleosis". Experiments with Setd8/Atg5 double knockout mice, demonstrated that endonucleosis requires the function of the autophagy machinery. Endonucleosis and hyperploidization are temporary, early features of senescence. Larger vesicles brake down into microvesicles over time and are eventually eliminated. The results reveal a senescence phenotype, which function as part of survival mechanisms to prevent necrotic death.

cell biology↗